Lucas Simon C C, Blackwell J Henry, Börjesson Ulf, Hargreaves David, Milbradt Alexander G, Ahmed Samiyah, Bostock Mark J, Guerot Carine, Gohlke Andrea, Kinzel Olaf, Lamb Michelle L, Selmi Nidhal, Stubbs Christopher J, Su Nancy, Su Qibin, Luo Haiou, Xiong Ting, Zuo Xiaoqian, Bazzaz Sana, Bienstock Corey, Centrella Paolo A, Denton Kyle E, Gikunju Diana, Guié Marie-Aude, Guilinger John P, Hupp Christopher, Keefe Anthony D, Satoh Takashi, Zhang Ying, Rivers Emma L
Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
ACS Med Chem Lett. 2024 May 20;15(6):791-797. doi: 10.1021/acsmedchemlett.4c00113. eCollection 2024 Jun 13.
Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.
Bfl-1在血液系统肿瘤和实体瘤中均过度表达；因此，非常需要Bfl-1的抑制剂。针对Bfl-1的DNA编码化学文库（DEL）筛选鉴定出了首个已知的Bfl-1可逆共价小分子配体。通过生物物理和生化技术验证了该结合，证实了其可逆共价作用机制，并表明是通过半胱氨酸55进行结合。这是首次从DEL筛选中鉴定出氰基丙烯酰胺可逆共价化合物，并突出了通过DEL筛选进行共价药物发现的更多机会。通过对命中化合物进行系统的构效关系探索，药效提高了10倍。更有效的类似物化合物成功地与Bfl-1共结晶，揭示了结合模式，并提供了与半胱氨酸55共价相互作用的进一步证据。
